Both thymidine and leucovorin can modulate the toxicity of methotrexate to normal and malignant tissues. The aim of this research is to determine whether differential thymidine protection of bone marrow can increase the therapeutic ration of methotrexate, particularly in comparison to selectivity achievable with leucovorin protection. These experiments will be carried out using tissue from human tumor xenografts growing in nude mice and samples of normal human marrow in colony-forming assays. If significant degrees of selectivity of thymidine protection are identified, the biochemical basis of this selectivity will be sought out using quantitative measurements of the activity of the thymidine salvage pathway in normal and malignant tissues.